Compounds and methods are known for control of pathogenic fungi. Of particular interest herein are certain peptidomimetic compounds useful to inhibit the enzyme N-myristoyl transferase which, in turn, is useful for selective control of the fungal organism Candida albicans. 
Candida albicans, a diploid asexual yeast, is a major cause of systemic fungal infections, particularly in patients with acquired immunodeficiency syndrome (AIDS).
Species of the genus Candida are part of the normal human flora and are the most common yeast pathogens. Candida albicans, a dimorphic, asexual yeast, is the most frequently identified pathogen among Candida species. Systemic Candida infections commonly occur in patients who have been immunocompromised by treatment with immunosuppressive medication and broad spectrum antibiotics.
At the present time, therapy for a patient afflicted with systemic C. albicans infection is treatment with amphotericin B alone or in combination with the nucleoside analog 5-fluorocytosine. Alternatively, lanosterol 14xcex1-demethylase inhibitors such as the imidazole ketoconazole or the triazole fluconazole are used. While amphotericin B is an effective fungicidal agent, it is nephrotoxic, does not penetrate into the cerebrospinal fluid, and must be given intravenously. Ketoconazole and the newer azoles are fungistatic rather than fungicidal.
A series of n-alkoxyacetic acids has been tested for effects on the growth of a variety of fungal species, including C. albicans, in Sabouraud dextrose agar, with 3-oxaundecanoic acid showing the broadest spectrum and highest potency and several other compounds, including 3-oxatetradecanoic acid, inhibiting growth [Gerson et al, J. Pharmaceut. Sci., 68, 82-84 (1979)].
U.S. Pat. No. 5,073,571 describes ether containing fatty acid compounds such as 13-oxatetradecanoic acid which have been evaluated as antiviral agents, e.g. against retroviruses such as HIV-1. The compound 13-oxatetradecanoic acid, which is a substrate for human acyl CoA synthetase and human myristoylCoA:protein N-myristoyltransferase (NMT), inhibits HIV-1 replication in acutely and chronically infected human T-lymphocyte cell lines at doses which do not cause cellular toxicity [B. Devadas et al, J. Biol. Chem., 267, 7224-7239 (1992)]. Studies with tritiated 13-oxatetradecanoic acid indicate that this fatty acid analog is incorporated into HIV-1 Pr55gag and nef and some, but not all, cellular proteins [Bryant et al, Proc. Nat""l. Acad. Sci. USA, 88, 2055-2059 (1991)].
N-myristoylation of proteins is catalyzed by myristoylCoA:protein N-myristoyltransferase (NMT1, N-myristoyltransferase). NMT transfers myristate (C14:0) from myristoylCoA to the amino-terminal Gly residue of proteins in such diverse eukaryotic species as animals, plants, and fungi [J. K. Lodge et al, J. Biol. Chem., 269, 2996-3000 (1994)]. This modification is required for the biological functions of a variety of cellular and viral proteins [D. R. Johnson et al, Ann. Rev. Biochem., in press, (1994)]. The NMT1 gene is essential for vegetative growth of S. cerevisiae. Moreover, haploid strains of S. cerevisiae containing a nmt1 null allele are not viable [R. J. Duronio et al, Proteins, Structure, Function, and Genetics, 13, 41-56 (1992c)]. Metabolic labeling studies indicate that S. cerevisiae produces at least 12 N-myristoylproteins during exponential growth [R. J. Duronio et al, J. Cell. Biol., 113, 1313-1330 (1991)]. Two functionally interchangeable ADP ribosylation factors, Arf1p and Arf2p, have been identified as N-myristoylproteins [T. Stearns et al, Mol. Cell. Biol., 10, 6690-6699 (1990)]. Metabolic labeling studies have shown that a laboratory strain of C.albicans (B311) synthesizes a small number of cellular N-myristoylproteins during exponential growth in rich media The C.albicans NMT gene has been isolated. Its 451 amino acid protein product shares 55% identity with the S. cerevisiae acyltransferase [R. C. Wiegand et al, J. Biol. Chem., 267, 8591-8598 (1992)]. Two ARF genes have also been indentified in C. albicans [C. A. Langner et al, J. Biol. Chem., 267, 17159-17169 (1992)]. At least one of them is a substrate for NMT [J. K. Lodge et al, J. Biol. Chem., 269, 2996-3000 (1994)]. Although C. albicans does not have a known sexual pathway, nonetheless it synthesizes a protein, Cag1, which is homologous to S. cervisiae Gpa1p [C. Sadhu et al, Mol. Cell. Biol., 12, 1977-1985 (1992)]. The amino termirnal sequence of Cag1 (GCGASVPVDD) makes it a likely substrate for S. cerevisiae Nmt1p [D. A. Towler et al, Ann. Rev. Biochem., 57, 69-99 (1988b)]. Moreover, CAG1 can complement the growth arrest and mating defects found in strains of S. cerevisiae with gpa1 null alleles [C. Sadhu et al, Mol. Cell. Biol., 12, 1977-1985 (1992)].
The peptide substrate specificities of C. albicans and S. cerevisiae NMTs are considerably different than that of human NMT [W. J. Rocque et al, J. Biol. Chem., 268, 9964-9971 (1993)]. However, surveys of a large panel of myristic acid analogs indicate that the acylCoA binding sites of the orthologous enzymes are quite similar [N. S. Kishore et al, J. Biol. Chem., 268, 4889-4902 (1993) footnote 2]. This apparent divergence in the peptide but not acylCoA binding sites undoubtedly reflects the similar requirements of these NMT enzymes for myristoylCoA and the marked differences in the numbers and types of protein substrates they must acylate in vivo [D. A. Rudnick et al, Adv. Enzvmol., 67, 375-430 (1993)].
Interaction between Saccharomyces-cerevisiae-derived myristoyl-CoA:protein N-myristoyltransferase (Nmt1p) and photoactivatable 125I-labeled octapeptides has been studied in the presence of other high-affinity peptide substrates and competitive inhibitors of such labeled octapeptides, such other peptide substrates and competitive inhibitors being the peptides GLYASKLS-NH2 and ALYASKLS-NH2, respectively [D. A. Rudnick et al, Proc. Natl. Acad. Sci., 90(3), 1087-1091 (1993)]
Peptidomimetic compounds, and pharmaceutical compositions thereof, for inhibition of the enzyme N-myristoyl transferase, provide selective control of the fungal organism Candida albicans, where such peptidomimetic compounds are selected from a class of compounds of Formula I: 
wherein R1 is selected from aminoalkyl, aminoalkylcycloalkyl, aminoalkylcycloalkylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminocycloalkylalkyl, dialkylaminocycloalkylalkyl, aminoalkylarylalkyl, monoalkylaminoalkylarylalkyl, dialkylaminoalkylarylalkyl, aminocycloalkyl, monocycloalkylaminoalkyl, monoalkylaminocycloalkyl, monocycloalkylaminocycloalkyl, dialkylaminocycloalkyl, aminocycloalkylarylalkyl, aminoalkylarylcycloalkyl, aminocycloalkylarylcycloalkyl, monocycloalkylaminoalkylarylalkyl, monoalkylaminocycloalkylarylalkyl, monoalkylaminoalkylarylcycloalkyl, monocycloalkylaminocycloalkylarylalkyl, monocycloalkylaminoalkylarylcycloalkyl, monoalkylaminocycloalkylarylcycloalkyl, monocycloalkylaminocycloalkylarylcycloalkyl, dialkylaminocycloalkylarylalkyl, dialkylaminoalkylarylcycloalkyl, dialkylaminocycloalkylarylcycloalkyl, heterocyclic-A-alkyl, heterocyclic-A-alkylarylalkyl, heterocyclic-A-cycloalkyl, heterocyclic-A-cycloalkylarylalkyl, heterocyclic-A-alkylarylcycloalkyl, heterocyclic-A-cycloalkylarylcycloalkyl, heteroaryl-A-alkyl, heteroaryl-A-alkylarylalkyl, heteroaryl-A-cycloalkyl, heteroaryl-A-cycloalkylarylalkyl, heteroaryl-A-alkylarylcycloalkyl and heteroaryl-A-cycloalkylarylcycloalkyl, wherein A is either a covalent bond or is a moiety selected from 
wherein R0 is selected from hydrido, alkyl, cycloalkyl and cycloalkylalkyl; wherein any foregoing heterocyclic-containing moiety may be fused to an aryl ring to form an arylheterocyclic moiety, and wherein any foregoing heteroaryl-containing moiety may be fused to an aryl ring to form an arylheteroaryl moiety, and wherein any of said heterocyclic moiety, heteroaryl moiety, arylheterocyclic moiety and arylheteroaryl moiety may be independently substituted at one or more substitutable positions with one or more radicals selected from halo, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, aminoacyl, aminocarbonylalkoxy, monoalkylamino, dialkylamino, alkoxy, alkylthio, aralkyl and aryl, with the proviso that said heterocyclic moiety is selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl, and with the further proviso that said heteroaryl moiety is selected from imidazolyl and pyridinyl;
wherein R2 is a radical selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, alkenyl, cycloalkenyl, fused bicycloalkenyl, cycloalkyl fused to cycloalkenyl, alkenylalkyl, alkynyl, aralkyl and aryl, wherein any of said R2 radicals having a substitutable position may be substituted by one or more radicals selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, fused bicycloalkenyl, cycloalkyl fused to cycloalkenyl, alkenylalkyl, alkynyl, halo, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, aralkoxy, aryloxy, arylthio, aralkyl, aryl, alkoxycarbonyl, cycloalkoxycarbonyl, alkoxycarbonylalkyl and cycloalkoxycarbonylcycloalkyl;
wherein Y is an alkylol group or is an acidic group selected to contain at least one acidic hydrogen atom so as to impart a pKa less than about 5.0 to compound of Formula I;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
Compounds of Formula I would be primarily useful in treating fungal infections caused by Candida albicans, particularly where selective inhibition of the NMT enzyme of this fungal organism is desirable over general NMT inhibition of the host, e.g., human subject. These compounds would also be useful as adjunctive therapies. For example, compounds of Formula I may be used in combination with other drugs, such as another anti-infective, e.g., metronidazole, to treat fungal infections.
The phrase xe2x80x9cacidic group selected to contain at least one acidic hydrogen atomxe2x80x9d, as used to define the xe2x80x94Y moiety, is intended to embrace chemical groups which, when attached at the xe2x80x9cC-terminusxe2x80x9d position of Formula I, confers acidic character to the compound of Formula I. xe2x80x9cAcidic characterxe2x80x9d means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a PKa in a range from about one to about six. More typically, the Formula I compound would have a pKa in a range from about one to about five. An example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (xe2x80x94COOH) attached directly to the xe2x80x9cC-terminusxe2x80x9d position. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as xe2x80x9cbioisosteres of carboxylic acidxe2x80x9d or referred to as xe2x80x9cacidic bioisosteresxe2x80x9d. Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I compound as conferred by the xe2x80x94Y moiety be in a range from about one to about five. The xe2x80x94Y moiety may be attached to the C-terminus position through any portion of the xe2x80x94Y moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the xe2x80x94Y acid moiety is tetrazole, the tetrazole is attached at the ring carbon atom.
A class of preferred peptidomimetic compounds are those compounds of Formula II: 
wherein R1 is selected from aminoalkyl, aminoalkylcycloalkyl, aminoalkylcycloalkylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminocycloalkylalkyl, dialkylaminocycloalkylalkyl, aminoalkylarylalkyl, monoalkylaminoalkylarylalkyl, dialkylaminoalkylarylalkyl, aminocycloalkyl, monocycloalkylaminoalkyl, monoalkylaminocycloalkyl, monocycloalkylaminocycloalkyl, dialkylaminocycloalkyl, aminocycloalkylarylalkyl, aminoalkylarylcycloalkyl, aminocycloalkylarylcycloalkyl, monocycloalkylaminoalkylarylalkyl, monoalkylaminocycloalkylarylalkyl, monoalkylaminoalkylarylcycloalkyl, monocycloalkylaminocycloalkylarylalkyl, monocycloalkylaminoalkylarylcycloalkyl, monoalkylaminocycloalkylarylcycloalkyl, monocycloalkylaminocycloalkylarylcycloalkyl, dialkylaminocycloalkylarylalkyl, dialkylaminoalkylarylcycloalkyl, dialkylaminocycloalkylarylcycloalkyl, heterocyclic-A-alkyl, heterocyclic-A-alkylarylalkyl, heterocyclic-A-cycloalkyl, heterocyclic-A-cycloalkylarylalkyl, heterocyclic-A-alkylarylcycloalkyl, heterocyclic-A-cycloalkylarylcycloalkyl, heteroaryl-A-alkyl, heeroaryl-A-alkylarylalkyl, heteroaryl- A-cycloalkyl, heteroaryl-A-cycloalkylarylalkyl, heteroaryl-A-alkylarylcycloalkyl and heteroaryl-A-cycloalkylarylcycloalkyl, wherein A is either a covalent bond or is a moiety selected from 
wherein R0 is selected from hydrido, alkyl, cycloalkyl and cycloalkylalkyl; wherein any foregoing heterocyclic-containing moiety may be fused to an aryl ring to form an arylheterocyclic moiety, and wherein any foregoing heteroaryl-containing moiety may be fused to an aryl ring to form an arylheteroaryl moiety, and wherein any of said heterocyclic moiety, heteroaryl moiety, arylheterocyclic moiety and arylheteroaryl moiety may be independently substituted at one or more substitutable positions with one or more radicals selected from halo, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, aminoacyl, aminocarbonylalkoxy, monoalkylamino, dialkylamino, alkoxy, alkylthio, aralkyl and aryl, with the proviso that said heterocyclic moiety is selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl, and with the further proviso that said heteroaryl moiety is selected from imidazolyl and pyridinyl;
wherein R2 is a radical selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, alkenyl, cycloalkenyl, fused bicycloalkenyl, cycloalkyl fused to cycloalkenyl, alkenylalkyl, alkynyl, aralkyl and aryl, wherein any of said R2 radicals having a substitutable position may be substituted by one or more radicals selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, fused bicycloalkenyl, cycloalkyl fused to cycloalkenyl, alkenylalkyl, alkynyl, halo, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, aralkoxy, aryloxy, arylthio, aralkyl, aryl, alkoxycarbonyl, cycloalkoxycarbonyl, alkoxycarbonylalkyl and cycloalkoxycarbonylcycloalkyl;
wherein Y is selected from hydroxyalkyl, hydroxycycloalkyl, hydroxycycloalkylalkyl, hydroxyaryl, hydroxyaminocarbonylaralkyl, hydroxyaminocarbonyl, hydroxyaminocarbonylalkyl, hydroxyaminocarbonylcycloalkyl, hydroxyaminocarbonylcycloalkylalkyl, hydroxyaminocarbonylaryl, carboxyl, carboxyalkyl, carboxycycloalkyl, carboxycyloalkylalkyl, tetrazolyl, tetrazolylalkyl, tetrazolylcycloalkyl, tetrazolylcycloalkylalkyl, phosphinic acid, monoalkylphosphinic acid, dialkylphosphinic acid, monocycloalkylphosphinic acid, dicycloalkylphosphinic acid, monocycloalkylalkylphosphinic acid, dicycloalkylalkylphosphinic acid, mixed monoalkylmonocycloalkylphosphinic acid, mixed monoalkylmonocycloalkylalkylphosphinic acid, mixed monocycloalkylmonocycloalkylalkylphosphinic acid, monoarylphosphinic acid, diarylphosphinic acid, mixed monoalkylmonoarylphosphinic acid, mixed monocycloalkylmonoarylphosphinic acid, mixed monocycloalkylalkylmonoarylphosphinic acid, phosphonic acid, alkylphosphonic acid, cycloalkylphosphonic acid, cycloalkylalkylphosphonic acid, aralkylphosphonic acid and arylphosphonic acid;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
A more preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, aminoalkylphenylalkyl, monoalkylaminoalkylphenylalkyl, dialkylaminoalkylphenylalkyl, heterocyclicalkyl, heterocyclicalkylphenylalkyl, heteroarylalkyl, heteroarylalkylphenylalkyl, heterocycliccylcoalkyl, heterocycliccycloalkylalkyl, heteroarylcycloalkyl and heteroarylcycloalkylalkyl wherein any foregoing heterocyclic moiety may be fused to a phenyl ring to form a benzoheterocyclic moiety and wherein any foregoing heteroaryl moiety may be fused to a phenyl ring to form a benzoheteroaryl moiety, and wherein any of said heterocyclic moiety, benzoheterocyclic moiety, heteroaryl moiety and benzoheteroaryl moiety may be substituted at one or more substitutable positions with one or more radicals selected from halo, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkylthio, phenylalkyl and phenyl; with the proviso that said heterocyclic moiety is selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl, and with the further proviso that said heteroaryl is selected from imidazolyl and pyridinyl;
wherein R2 is a radical selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl, wherein any of said R2 radicals having a substitutable position may be substituted by one or more radicals selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, alkylthio, phenylalkyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, naphthylalkyl, tetrahydronaphthylalkyl, decahydronaphthylalkyl, naphthylcycloalkyl, tetrahydronaphthylcycloalkyl, decahydronaphthylalkyl, alkoxycarbonyl and alkoxycarbonylalkyl;
wherein Y is selected from 
xe2x80x83wherein each of R4 through R8 is either a covalent bond or is a divalent radical of the general structure 
wherein X is selected from alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl;
wherein R9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
An even more preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from 
wherein W is a divalent radical of the general structure 
wherein W is selected from alkyl and cycloalkyl;
wherein each of R10 and R11 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl; wherein further R10 and R11 may be taken together to form a saturated heterocyclic ring system having five or six ring members and having at least one nitrogen atom as a ring member and optionally having a second heteroatom selected from an oxygen, nitrogen or sulfur atom as a ring member, said heterocyclic ring system selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl; wherein each of R12 and R13 is independently selected from hydrido, alkyl and haloalkyl; wherein R14 is selected from hydrido, alkyl, haloalkyl, halo, cycloalkyl, alkoxy, alkylthio, phenylalkyl and phenyl;
wherein R2 is a moiety selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, naphthylalkyl, tetrahydronaphthylalkyl, decahydronaphthylalkyl, naphthylcycloalkyl, tetrahydronaphthylcycloalkyl, decahydronaphthylalkyl, phenylalkyl and phenyl, wherein any said R2 moiety may be substituted at a substitutable position by one or more radicals selected from alkyl, halo and alkoxy;
wherein Y is selected from 
xe2x80x83wherein each of R4 through R8 is either a covalent bond or is a divalent radical of the general structure 
xe2x80x83with each of R4 through R8 independently selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2CH2CH2xe2x80x94;
wherein R9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
A highly preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from 
wherein each of R10 and R11 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl; wherein further R10 and R11 may be taken together to form a saturated heterocyclic ring system having five or six ring members and having at least one nitrogen atom as a ring member and optionally having a second heteroatom selected from an oxygen, nitrogen or sulfur atom as a ring member, said heterocyclic ring system selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl; wherein each of R12 and R13 is independently selected from hydrido, alkyl and haloalkyl; wherein R14 is selected from hydrido, alkyl, haloalkyl, halo, cycloalkyl, alkoxy, alkylthio, phenylalkyl and phenyl;
wherein each of m, n, p and r is a whole number independently selected from 3 through 15; wherein each of q and t is a whole number independently selected from 1 through 6;
wherein R2 is a moiety selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, naphthylalkyl, tetrahydronaphthylalkyl, decahydronaphthylalkyl, naphthylcycloalkyl, tetrahydronaphthylcycloalkyl, decahydronaphthylalkyl, phenylalkyl, and phenyl, wherein any said R2 moiety may be substituted at a substitutable position by one or more radicals selected from alkyl, halo and alkoxy;
wherein Y is selected from 
xe2x80x83wherein each of R4 through R8 is either a covalent bond or is a divalent radical of the general structure 
xe2x80x83with each of R4 through R8 independently selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2CH2CH2;
wherein R9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl and benzyl;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
A more highly preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from 
wherein each of R10 and R11 is independently selected from hydrido and alkyl; wherein further R10 and R11 may be taken together to form a saturated heterocyclic ring system having five or six ring members and having at least one nitrogen atom as a ring member and optionally having a second hetero atom selected from an oxygen, nitrogen or sulfur atom as a ring member, said heterocyclic ring system selected from morpholino, thiomorpholino, piperazinyl, piperidinyl and pyrrolidinyl; wherein each of R12 and R13 is independently selected from hydrido, alkyl and haloalkyl; wherein R14 is selected from hydrido, alkyl, haloalkyl, halo, cycloalkyl, alkoxy, alkylthio, phenylalkyl and phenyl;
wherein each of m, n, p and r is a whole number independently selected from 6 through 14; wherein each of q and t is a whole number independently selected from 3 through 6;
wherein R2 is a moiety selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, naphthylalkyl, tetrahydronaphthylalkyl, decahydronaphthylalkyl, naphthylcycloalkyl, tetrahydronaphthylcycloalkyl, decahydronaphthylalkyl, phenylalkyl, and phenyl, wherein any said R2 moiety may be substituted at a substitutable position by one or more radicals selected from alkyl, halo and alkoxy;
wherein Y is selected from 
xe2x80x83wherein each of R4 through R8 is either a covalent bond or is a divalent radical of the general structure 
xe2x80x83with each of R4 through R8 independently selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2CH2CH2;
wherein R9 is selected from hydrido, alkyl and benzyl;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
An even more highly preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from 
wherein each of R10 and R11 is independently selected from hydrido and alkyl; wherein each of R12 and R13 is independently selected from hydrido and alkyl; wherein R14 is selected from hydrido, alkyl, haloalkyl, alkoxy and alkylthio;
wherein each of m, n, p and r is a whole number independently selected from 6 through 14; wherein each of q and t is a whole number independently selected from 3 through 6;
wherein R2 is a moiety selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, haloalkyl, naphthyl, naphthylalkyl, phenylalkyl, and phenyl, wherein any said R2 moiety may be substituted at a substitutable position by one or more radicals selected from alkyl, halo and alkoxy;
wherein Y is selected from 
xe2x80x83wherein each of R4 through R8 is either a covalent bond or is xe2x80x94CH2;
wherein R9 is selected from hydrido, alkyl and benzyl;
or a pharmaceutically-acceptable ester, amide, or salt thereof.
A very highly preferred class of peptidomimetic compounds consists of those compounds of Formula II wherein R1 is selected from
H2N(CH2)9xe2x80x94, H2N(CH2)10xe2x80x94, H2N(CH2)11xe2x80x94, CH3NH(CH2)10xe2x80x94, (CH3)2N(CH2)10xe2x80x94, p-[H2N(CH2)6]C6H4CH2xe2x80x94, p-[H2N(CH2)8]C6H4CH2xe2x80x94, p-[H2N(CH2)9]C6H4CH2xe2x80x94, p-[H2N(CH2)10]C6H4CH2xe2x80x94, p-[H2N(CH2)6]C6H4CH(CH3)xe2x80x94, p-[H2N(CH2)8]C6H4CH(CH3)xe2x80x94, p-[H2N(CH2)9]C6H4CH(CH3)xe2x80x94, p-[H2N(CH2)10]C6H4CH(CH3)xe2x80x94, 
wherein R2 is selected from xe2x80x94H, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH2CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -Cyclo-C7H13, -cyclo-C8H15, xe2x80x94CH(CH3)(CH2CH3), xe2x80x94CH(CH2CH3)2, xe2x80x94CH(CH3)(CH2CH2CH3), xe2x80x94C(CH3)3, HCxe2x89xa1CCH2xe2x80x94, H2Cxe2x95x90CHxe2x80x94, H2Cxe2x95x90CHCH2xe2x80x94, xe2x80x94CH2F, xe2x80x94CH2C6H5, xe2x80x94CH2C6H4-p-OCH3, xe2x80x94CH2C6H4-p-CH3, xe2x80x94CH2C6H4-p-F, xe2x80x94CH2CH2C6H5, xe2x80x94CH2-cyclo-C6H11, xe2x80x94CH2-cyclo-C6H10-4-F, xe2x80x94CH2-cyclo-C6H10-4-CH3, xe2x80x94CH2-cyclo-C6H10-4-OCH3, xe2x80x94-CH2CH2-cyclo-C6H11, xe2x80x94CH2 -cyclo-C5H9, xe2x80x94CH2CH2-cyclo-C5H9 and xe2x80x94CH2-2-naphthyl;
wherein Y is selected from xe2x80x94CO2H, xe2x80x94CH2CO2H, xe2x80x94CONHOH, xe2x80x94PO3H2, and 
or a pharmaceutically-acceptable ester, amide, or salt thereof.
A very highly preferred class of peptidomimetic compounds of Formula II of particular interest consists of compounds and their diastereoisomers of the group consisting of
L-Alanine, 3-cyclohexyl-N-[N2-[N-[2-[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]oxopropyl]-L-seryl]-L-lysyl]-, (xc2x1), bis-trifluoroacetate;
L-Alanine, 3-cyclohexyl-N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyllacetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-Alanine, 3-cyclohexyl-N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-Leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-Alanine, N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-Alanine, 3-phenyl-N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-iso-Leucine, N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
L-Leucine, N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate;
Lysinamide, N-[1-cyclohexyl-2-carboxyethyl]-N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-, xc2x1, bis-trifluoroacetate;
Lysinamide, N-[1-cyclooctyl-2-carboxyethyl]-N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-, xc2x1, bis-trifluoroacetate; and
D-Alanine, 3-cyclohexyl-N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-seryl]-L-lysyl]-, bis-trifluoroacetate.
The term xe2x80x9chydridolxe2x80x9d denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a 
group; or, as another example, two hydrido groups may be attached to a carbon atom to form a xe2x80x94CH2xe2x80x94 group. Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d, the term xe2x80x9calkylxe2x80x9d embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term xe2x80x9chaloalkylxe2x80x9d, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term xe2x80x9chaloalkylxe2x80x9d are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3-tetrafluoropropyl groups. The term xe2x80x9cdifluoroalkylxe2x80x9d embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The terms xe2x80x9calkylolxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety. The term xe2x80x9calkynylxe2x80x9d embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term xe2x80x9ccycloalkenylxe2x80x9d embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as a methoxy group. The term xe2x80x9calkoxyalkylxe2x80x9d also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkoxyalkylxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl.groups. The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl and biphenyl. A preferred aryl group is phenyl. The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms xe2x80x9cbenzylxe2x80x9d and xe2x80x9cphenylmethylxe2x80x9d are interchangeable. The terms xe2x80x9caryloxyxe2x80x9d and xe2x80x9carylthioxe2x80x9d denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The term xe2x80x9caralkoxyxe2x80x9d, alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term xe2x80x9calkenylalkyllxe2x80x9d denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term xe2x80x9cacylxe2x80x9d whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. xe2x80x9cLower alkanoylxe2x80x9d is an example of a more prefered sub-class of acyl. A group embraced by the term xe2x80x9cheterocyclic ring systemxe2x80x9d or xe2x80x9cheteroaryl ring systemxe2x80x9d, or xe2x80x9cheterocyclicxe2x80x9d, or xe2x80x9cheteroarylxe2x80x9d may be attached to the backbone of Formula I as a substituent at R1 through a carbon atom of the hetero ring system, or may be attached through a carbon iatom of a moiety substituted on a hetero ring-member carbon atom. Also, such hetero-containing group may be attached through a ring nitrogen atom, where a bond is formable with such nitrogen atom. For any of the foregoing defined radicals, preferred radicals are those containing from one to about ten carbon atoms.
The term xe2x80x9cmonoalkylphosphinic acidxe2x80x9d is intended to describe an acidic moiety having one alkyl group attached to the phosphorus atom through which alkyl group the phosphinic moiety is attached to the Formula I nucleus at xe2x80x9cYxe2x80x9d. In such cases, this alkyl group will be xe2x80x9cdivalentxe2x80x9d in character as shown below: 
Another phospinic acid moiety described for use as xe2x80x9cYxe2x80x9d substituent is characterized by the term xe2x80x9cdialkylphosphinic acidxe2x80x9d moiety, which term is intended to describe an acidic moiety having two alkyl groups attached to the phosphorous atom, one of such alkyl groups being xe2x80x9cdivalentxe2x80x9d in character and through which this dialkylphosphinic acid moiety is attached at xe2x80x9cYxe2x80x9d, as shown below: 
The phrase xe2x80x9cmixed monoalkylmonocycloalkylphosphinic acidxe2x80x9d is intended to describe a phosphinic acid moiety having both a monoalkyl moiety and a monocycloalkyl moiety attached to the phosphorus atom, either of which may provide a xe2x80x9clinkingxe2x80x9d divalent group to the nucleus of Formula I at the xe2x80x9cYxe2x80x9d position.
Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl-, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.
Also included in the family of compounds of Formula I, are isomeric forms including regioisomers, optical isomers, diastereoisomers and epimers, as well as the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicylic, phenylacetic, trifluoroacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, xcex2-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
Nomenclature used to define the peptides of Formula I is that specified by the IUPAC [published in European Journal of Biochemistry, 138, 9-37 (1984)], wherein conventional representation of the peptides stipulates that in a peptide sequence the amino group appears to the left and the carboxyl group to the right. When the amino acid has enantiomeric forms, it is the L form of the amino acid which is represented unless otherwise stated. In the amino acid structural formulas, each residue is generally represented by a single or 3-letter designation, corresponding to the trivial name of the amino acid in accordance with the following list:
Another name for norvaline in n-propylglycine. The group 125I-Tyr indicates a radioactive mono-iodinated tyrosine residue.
The compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedures as schematically shown in Schemes I-VIII. 
An appropriate DL-, D-, or L-lysine derivative 1 which has been differentially protected at both the alpha and omega amino groups with a suitable amine protecting group designated P1 or P2 is coupled to a suitably protected DL-, D-, or L-amino acid ester 2 containing an appropriate amino acid carboxyl-protecting group designated P3 in a suitable solvent to produce a protected lysinamide of formula 3, wherein R2, P1, P2, and P3 are as defined above. Such reactions are well-known to those skilled in the art of solution-based peptide synthesis and generally employ methods such as those described by Bodanszky, M. and Bodanszky, A. in xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d (1984), Springer-Verlag, New York, N.Y. or by Bodanszky, M. in xe2x80x9cPrinciples of Peptide Synthesisxe2x80x9d (1984), Springer-Verlag, New York, N.Y., and references cited therein.
Alternatively, the compounds of Formula I can be prepared according to Scheme I using well-known methods in solid-phase peptide synthesis such as those described by Barany, G. and Merrifield, R. B. in xe2x80x9cThe Peptidesxe2x80x9d (Gross, E. and Meienhofer, J., Eds.), vol.2, pp.1-284, (1979), Academic Press, New York, N.Y., and references cited therein. In this case, the carboxyl-protecting group designated P3 is covalently attached, usually by an ester bond, to an appropriate solid phase resin, such as a hydroxymethyl-resin composed of styrene/1% divinylbenzene (Peninsula Laboratories) or an O-methlyphenylacetamidomethyl-resin (Sigma). Such resins are commercially available or can be readily prepared by one skilled in the art of solid-phase peptide synthesis.
Suitable amino protecting groups are well known in the art and include carbobenzoxy, 4-chloro-benzoxycarbonyl, t-butoxycarbonyl, and the like. P1 and P2 independently are selected from amine protecting groups, including but not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl, and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxy-carbonyl, aralkoxy-carbonyl and silyl. Examples of aralkyl include, but are not limited to benzyl, orthomethyl-benzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl of C1-C8, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino, acylamino, and acyl, or their salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthalenyl, indanyl, anthracenyl, durenyl, 9-phenylfluorenyl, and phenanthrenyl, cycloalkenylalkyl or substituted cycloalkenylalkyl radicals containing cycloalkyls of C6-C10. Suitable acyl groups include carbobenzoxy, 4-chloro-benzoxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl and the like.
One skilled in the art can choose appropriate combinations of P1 and P2. For example, a preferred amino protecting group for P1 is carbobenzoxy and a preferred amino protecting group for P2 is t-butoxycarbonyl. Alternatively, a preferred amino protecting group for P1 is t-butoxycarbonyl and a preferred amino protecting group for P2 is carbobenzoxy.
Additionally, the P1 and/or P2 protecting groups can form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis-(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl, and the like, and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mon-. di-, or tri-substituted e.g., nitrophthalimidyl.
The term silyl refers to a silicon atom optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis-(dimethylsilyl)ethane, and diphenylmethylsilyl.
Suitable carboxyl-protecting groups P3 are well known in the art and include methyl, ethyl, benzyl, tertiary-butyl, 4-methoxyphenylmethyl, and the like.
The DL-, D-, or L-amino acid ester corresponding to formula 2 wherein R2 and P3 is as defined above are commercially available (Sigma Chemical Co.), or are readily prepared using standard methods well known in the art from readily available starting materials. Methods of preparing these amino acid derivatives from the corresponding amino acids are well known to those skilled in the art of organic chemistry including amino acid/amino acid ester chemistry using methods such as those described by R. M. Williams in xe2x80x9cSynthesis of Optically Active xcex1-Amino Acids,xe2x80x9d (1989) Pergamon Press, New York, N.Y.
Standard coupling procedures can be used to couple the amino acids and amines. The carboxylic acid group is reacted to form an anhydride, mixed anhydride, acid halide, such as chloride or bromide, or active ester, such as esters of N-hydroxysuccinimide, HOBT (W. Kxc3x6nig, R. Geiger, Chem. Ber. 103, 788 (1970), and the like, using well known procedures and conditions. This reaction is usually facilitated by adding an acid scavenger such as a teritary amine base. Suitable acid scavengers include, but are not limited to triethylamine, tributylamine, tri-iso-propylamine, DBU, N-methylmorpholine, di-iso-propylethylamine, pyridine, 2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, and the like, including mixtures of these bases. A preferred tertiary amine base is N-methylmorpholine. Appropriate solvent systems include tetrahydrofuran, ethylether, methyl-tert-butylether, methylene chloride, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, including mixtures thereof.
Following preparation of the lysinamide drivative 3, the amino protecting group P1 is removed under conditions which will not effect the remaining portion of the molecule to produce the lysinamide 4, where R2, P2, and P3 are as defined above. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method (W. H. Hartung, and R. Simonoff, Organic Reactions, 7, 263-326, (1953)) involves removal of the protecting group, e.g., removal of a carbobenzoxy group, by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. When the P1 protecting group is a t-butoxycarbonyl group, it can be removed utilizing an inorganic or organic acid, e.g., HF, HCl or trifluoroacetic acid (H. Kappeler, and R. Schwyzer, Helv. Chim. Acta, 43, 1453, (1960)), in a suitable solvent system such as dioxane or methylene chloride. The resulting product is the lysine salt derivative.
Following neutralization of the salt, the amine 4 is then coupled to a suitably protected DL-, D-, or L-serine derivative 5, where P4 is an appropriate hydroxyl-protecting group and P1 is a suitable amino protecting group, as defined above, in an appropriate solvent to provide the desired protected serine-lysine dipeptide derivatives6, where R2, P1, P2, P3, and P4 are as defined above. Examples of a suitable P4 hydroxyl-protecting group include, but are not limited to tert-butyl and benzyl, and the like. In general, tert-butyl is preferred for P4 under solution conditions, while benzyl is preferred for P4 using solid phase synthetic methods.
Following preparation of the protected serine-lysine dipeptide 6, the amino protecting group P1 is then removed under conditions that will not effect the rest of the molecule, using the general methods described above for the deprotection of 3, to provide the amine 7.
The resulting amine 7 is then coupled under standard conditions with an appropriate carboxylic acid 8, where R1 is as defined above, in a suitable solvent to provide the protected amide 9. General procedures for the synthesis of these carboxylic acids 8 containing the appropriate R1 groups are shown schematically in Schemes VII and VIII.
Following preparation of the protected amide 9, the carboxyl-protecting group P3 is removed by base hydrolysis under standard conditions, using a solution of an appropriate metal hydroxide, such as lithium or sodium hydroxide, in an appropriate aprotic or protic solvent system such as an alcohol or water and the like or mixtures thereof, to provide the free carboxylic acid 10 after acidification. Alternatively, when P3 is a benzyl or other aralkyl group, it may be removed by hydrogenolysis under standard conditions, using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. Alternatively, when P3 is a tert-butyl group, it can be removed utilizing an organic or inorganic acid, e.g., HF, HCl or trifluoroacetic acid, in an appropriate solvent system such as dioxane or methylene chloride.
Following preparation of the protected carboxylic acid 10, the remaining P2 and P4 protecting groups can be removed under standard conditions as described above under conditions which do not effect the rest of the molecule to provide the deprotected dipeptide carboxylic acid derivatives 11. Alternatively, the sequence of reactions leading from 9 to 11 can be reversed, wherein the protecting groups P2 and P4 are removed first under conditions which do not effect the rest of the molecule, and then the carboxyl-protecting group P3 can be removed subsequently, under suitable conditions as described above. Alternatively under solid phase conditions, the protecting group P2 is removed first under conditions which do not effect the rest of the molecule, and then the carboxyl-protecting group P3 and hydroxyl-protecting group P4 can be removed subsequently, under suitable conditions using HF, as described above. In either case, the resulting final products 11 or their derivatives or salts can be crystallized or purified chromatographically using either a chiral or achiral column as is well known to those skilled in the art.
Alternatively, the sequence of coupling and deprotection reactions leading to intermediate 9 can be altered as depicted in Scheme II.
Starting from a suitable xcex5-amino protected lysine derivative 12, subsequent coupling to the protected serine derivative 5 produces the protected dipeptide 13, wherein P1, P2, P3, and P4 are as defined above. The amino protecting group P1 in 13 is then removed under conditions which do not alter the rest of the molecule, and the resulting amine 14 is then coupled under standard conditions with 8 to provide 15. Subsequent removal from 15 of the carboxyl-protecting group P3, usually by hydrolysis, provides the free carboxylic acid 16, which can be subsequently activated and coupled with 2 under standard conditions to provide intermediate 9, wherein R1, R2, P2, P3, and P4 are as defined above. Similar methods to those described previously in the reactions in Scheme I can then be used to convert 9 to 11 under standard conditions. 
Alternatively, as depicted in Scheme III, intermediate 16 can be activated and coupled under standard conditions with a suitably protected DL-, D-, or L-beta-amino acid ester 17 to provide the protected intermediate 18. Representative N-protected beta-amino acid esters are well known to those skilled in the art of amino acid ester chemistry and can be readily prepared using the methods described by E. Juaristi, D. Quintana and J. Escalante in Aldrichimica Acta, 27, 3-11 (1994), and references cited therein. Subsequent deprotection or hydrolysis removes the carboyl-protecting group P3 from 18 to provide the free carboxylic acid derivative 19, which can be subsequently deprotected under the conditions described above for Scheme I to provide the homologated DL-, D-, or L-beta-amino acid analog 20. 
Alternatively, intermediate 16 can be activated and coupled with a suitably protected phosphono-amino acid ester 21 to provide the coupled phosphonate ester product 22. Representative protected phosphono-amino acid esters 21 are well know to those skilled in the art of organophosphorus chemistry and can be readily prepared using the methods described by G. Osapay and A. Csiba in Eur. J. Med. Chem. 28, 355-61 (1993), R. G. Almquist, W.-R. Chao, and C. Jennings-White in J. Med. Chem. 28, 1064, (1985), T. Yokomatsu and S. Shibuya in Tetrahedron: Asymmetry, 3, 377-8 (1992), and M. C. Allen, W. Fuhrer, B. Tuck, R. Wade and J. M. Wood in J. Med. Chem. 32, 1652-61 (1989), and references cited therein. Subsequent hydrolysis removes the P3 phosphonate-protecting groups from 22 to produce the phosphonic acids 23, which can be further deprotected under standard conditions as described previously to provide the fully-deprotected phosphonic acids 24. 
Alternatively, intermediate 16 can be activated and coupled with a suitably N-protected tetrazole 25 to provide the coupled protected tetrazole product 26. Representative N-protected tetrazoles 25 are well known to those skilled in the art of amino acid chemistry and can be readily prepared from the corresponding protected aminoalkyl tetrazoles as described by Z. Grzonka, E. Bekowskas, and B. Liberek in Tetrahedron, 27, 1783 (1971), and by L. R. Hughes, J. Oldfield, S. J. Pegg, A. J. Barker and P. R. Marsham in European Patent EP 373891. Subsequent deprotection of 27 under standard conditions, as described previously, provides the fully deprotected tetrazoles 28. 
Alternatively, intermediate ester 9 can be reacted with a suitably protected hydroxylamine derivative in a suitable solvent to provide the coupled hydroxyl-protected hydroxamic acid product 29, as described by E. W. Petrillo and M. A. Ondetti in U.S. Pat. No. 4,284,561 (1981). Representative oxygen-protected hydroxylamines are commercially available or readily prepared by those skilled in the art. Subsequent deprotection of 29 can be accomplished under standard conditions either stepwise through intermediate 30 or directly to provide the fully deprotected hydroxamic acid analogs 31. 
The intermediate carboxylic acids 8 required for the syntheses depicted in Schemes I-VI are either commercially available or readily prepared by those skilled in the art of organic synthesis. Representative general procedures for the preparation of these intermediates 8 are depicted in Schemes VII and VIII.
Commercially available p-iodophenyl acetic acid 32 is esterified with an alcohol, preferably methanol, under standard conditions to provide the 
corresponding methyl p-iodophenylacetate 33. The iodo-ester 33 is then coupled with an appropriate acetylenic alcohol 34 to provide the coupled alcohol product 35 under conditions utilizing a palladium catalyst as described by K. Sonogashira, Y. Tohda and N. Hagihara in Tetrahedron Letters, 50, 4467-70 (1975). This reaction may be applied to a variety of acetylenic alcohols where the number of methylene units defined by x may be varied between 1 and 9. The resulting unsaturated alcohol 35 is then reduced by hydrogenolysis in the presence of a suitable catalyst such as palladium on carbon to provide the saturated alcohol product 36, which can be cleanly converted to the corresponding saturated iodide 37, under standard conditions using known alcohol group manipulations.
The iodide ester 37 may be hydrolyzed with base to provide the corresponding free carboxylic acid 38, after acidification, which is then reacted with a suitable nitrogen heterocycle in the presence of base and in a suitable aprotic solvent to give the coupled carboxylic acid product 39, after acidification. Essentially any acid scavenger, such as sodium hydride or a tertiary amine as previously defined, may be used in this reaction. Sodium hydride is the preferred base. Examples of suitable heterocycles include, but are not limited to, 1,2,4-triazole, 1,2,3-triazole, imidazole, benzimidazole, 2-mercapto-pyridine, N-methyl-2-mercaptoimidazole, 2-mercaptobenzimidazole, or 1,2,4-triazole, 1,2,3-triazole, imidazole, or benzimidazole systems substituted with halo, alkyl or alkoxy groups. Preferably, the heterocycle is an imidazole or benzimidazole ring; most preferred is a 2-methylimidazole.
Alternatively, the iodide ester 37 can be converted stepwise to the corresponding amino ester 42 after formation and reduction of the corresponding azide intermediate 41. Amino ester 42 is then N-protected with a suitable amino protecting group, P1, as defined above, to provide 43. Preferably, P1 is a t-butoxycarbonyl (BOC) group, as depicted in Scheme VII. The resulting N-protected amino ester 43 is then hydrolyzed under standard conditions to give the N-protected amino acid 44, after acidification.
Alternatively as shown in Scheme VIII, the iodophenylacetate ester 33 can be alkylated xcex1 to the ester group with a suitable alkyl halide Rxe2x80x2X in an aprotic solvent and in the presence of base such as sodium hydride to provide the racemic iodophenyl alkanoate esters 45. Preferably Rxe2x80x2 is a primary lower alkyl group such as methyl. The resulting product 45 can then be carried through the same sequence of reactions as previously described for those in Scheme VII to provide the a-alkyl substituted intermediates 46-55. 
The following is a description of preparation of a compound (Comparator Compound xe2x80x9cAxe2x80x9d) which is not part of the present invention. Following this synthesis description is a table of data obtained by evaluation of Comparator Compound xe2x80x9cAxe2x80x9d in accordance with the methods described in the xe2x80x9cBiological Evaluationxe2x80x9d section. 
Part A:
To commercially available (Peninsula Laboratories) hydroxymethyl-resin of styrene/1% divinylbenzene (0.67 g, 0.75 mequiv/g) in 10 mL of dichloromethane was added N-BOC-(3-cyclohexyl)-D-alanine (0.55 g, 2.0 mmoles), dicyclohexylcarbodiimide (DCC, 0.4 g, 2.0 mmoles), and 4-dimethyl-aminopyridine (DMAP, 0.02 g, 0.2 mmoles). After stirring for 18 hours at room temperature, the amino acid-resin was separated by filtration and treated with 20 mL of 50% trifluoroacetic acid in dichloromethane for 30 minutes, and separated by filtration. The resulting amino acid-resin was washed sequentially with dichloromethane (3xc3x9720 mL), isopropanol (3xc3x9720 mL), diisopropylethylamine 10% (v/v) in dichloromethane (3xc3x9720 mL), and dichloromethane (3xc3x9720 mL).
Part B:
N-xcex1-BOC-N-xcex5-(2-chloro-benzyloxycarbonyl)-D-lysine (0.83 g, 2.0 mmoles) was activated with dicyclohexylcarbodiimide (0.20 g, 1.0 mmoles) in dichloromethane and coupled to the resin product from Part A for 60 minutes at room temperature. The dipeptide-resin was separated by filtration, the N-xcex1-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was washed as described in Part A.
Part C:
N-BOC-(O-benzyl)-D-serine (0.59 g, 2.0 mmoles) was activated with dicyclohexylcarbodiimide (0.20 g, 1.0 mmoles) in dichloromethane and coupled to the resin product from Part B for 60 minutes at room temperature. The tripeptide-resin was separated by filtration, the N-xcex1-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was washed as described in Part A.
Part D:
To 4-[(2-methyl-1H-imidazol-1-yl)butyl]phenylacetic acid hydrochloride (0.08 g, 0.26 nmoles) in 2 mL of dimethylformamide (DMF) was added diisopropyl-ethylamine (0.04 mL, 0.26 mmoles). The resulting mixture was added to a suspension of the tripeptide-resin product from Part C in 5 mL of dichloromethane, followed by the addition of dicyclohexylcarbodiimide (0.05 g, 0.26 nmoles). After 18 hours at room temperature, the solvent was removed by filtration, and the resulting resin was washed with dichloromethane.
Part E:
The resin product from Part D was treated with 10 mL of 90% hydrogen fluoride in anisole (v/v) for 60 minutes at 0xc2x0 C. The hydrogen fluoride was removed by evaporation, the resulting residue was extracted with 30% acetic acid in water and lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 53 mg of 95% pure (by HPLC) D-alanine, 3-cyclohexyl-N-[N2-[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-D-seryl]-D-lysyl]-, bis-trifluoroacetate; HRMS: (M+H) calcd. 641.4027, found 641.4038.
The following procedures constitute specific exemplification of methods to prepare starting materials, intermediates and product compounds embraced by the foregoing General Synthetic Schemes. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare the compounds of the invention. All temperatures expressed are in degrees Centigrade.